Journal of

Clinical Medicine
ArticleChanges in Body Weight in Severely Obese Patients Treated with
the Anorexiant Mazindol
Yoshimitsu Tanaka 1 , Norikazu Maeda 1,2 , Masahiro Koseki 1,3
1
2

3

*

and Kazuhisa Maeda 1, *Longwood Maeda Clinic, Suita 565-0874, Japan
Department of Endocrinology, Metabolism and Diabetes, Faculty of Medicine, Kindai University,
Osaka-Sayama 589-8511, Japan
Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of
Medicine, Suita 565-0871, Japan
Correspondence: kaz@kitasenri-maeda-cl.com; Tel.: +81-6-6832-8635

Abstract: (1) Background: The number of severely obese patients worldwide is rapidly increasing.
Recently, novel therapeutic approaches, such as bariatric surgery or GLP-1 receptor agonists, haveemerged, bringing about a paradigm shift in this field. However, these therapies sometimes facechallenges, such as peri-surgical complications or supply shortages. Mazindol, which is an appetite
suppressant approved decades ago in Japan, remains a valuable option. In this study, we investigatedthe effectiveness of mazindol in reducing body weight in 147 patients, and we examined the factors
influencing said effectiveness. (2) Methods: The patients were divided into four groups based on thetreatment cycles they underwent: 1 cycle, 2 cycles, 3–5 cycles, and over 6 cycles. We compared thechanges in body weight before and after the treatment among these four groups. Additionally, wesought to identify the factors correlated to the effectiveness of mazindol. (3) Results: The change inbody weight was more pronounced in the group which underwent 3–5 cycles compared to the groups
which underwent 1 cycle and 2 cycles; this change was also more pronounced in the group which
underwent over 6 cycles compared to those which underwent 1 cycle. Furthermore, we observed
a significant correlation between the initial body weight and the extent of body weight change.
(4) Conclusions: Mazindol demonstrated effectiveness in reducing the body weight of patients in acycle-dependent manner.
Citation: Tanaka, Y.; Maeda, N.;
Koseki, M.; Maeda, K. Changes in

Keywords: mazindol; obesity; anorexiant

Body Weight in Severely Obese
Patients Treated with the Anorexiant
Mazindol. J. Clin. Med. 2024, 13, 1860.
https://doi.org/10.3390/jcm13071860

Academic Editor: Gangyi Yang
Received: 4 March 2024
Revised: 17 March 2024
Accepted: 20 March 2024
Published: 23 March 2024

Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction
The global prevalence of obesity has reached alarming levels [1], necessitating effective strategies for weight reduction. Patients with severe obesity (BMI over 35) are at ahigher risk of developing complications such as type 2 diabetes [2,3], hypertension [4],cardiovascular disease [5,6], and hypoventilation [7,8], among others. Therapies aimed
at reducing body weight are crucial in preventing these illnesses. However, achieving
a significant weight loss is often challenging [9]. Metabolic and bariatric surgeries haveemerged as viable therapeutic options for severe obesity that has proved unresponsive to
traditional diet and exercise interventions. A recent report from Kimura et al. has shownthat metabolic and bariatric surgeries can change patients’ eating behaviors [10].
Despite its potential, the effectiveness of this surgical approach varies widely among
patients, with some individuals experiencing minimal weight reduction or none at all [11].
Moreover, psychiatric complications—including the exacerbation of pre-existing mental illness, like depression—can occur in patients who undergo these surgical procedures [12–14].
In light of these challenges, anorexiant agents have long been recognized as a secondline treatment option, alongside metabolic and bariatric surgeries, according to the latest
Japanese guidelines on the treatment of obesity [15]. Anorexiant agents offer the potential
for safe and effective weight loss, the alleviation of obesity-related complications, and

J. Clin. Med. 2024, 13, 1860. https://doi.org/10.3390/jcm13071860

https://www.mdpi.com/journal/jcm

J. Clin. Med. 2024, 13, 1860

2 of 10a reduction in polypharmacy [16]. However, the development of effective anorexiant
agents has been hindered by insufficient efficacy and the emergence of severe side effects.
While several anorexiant agents have gained approval from the U.S. Food and Drug
Administration (FDA), mazindol has remained, for decades, the only approved anorexiant
in Japan for highly obese patients, that is, until the recent approval of semaglutide. Despite
its approval over 30 years ago, there is limited evidence regarding the clinical efficacy ofmazindol worldwide. This is probably because its use is limited to a few countries, such as
Japan, Canada, Mexico, and several countries in Middle and South America. Although twostudies regarding the use of mazindol in Mexico have recently been published [17,18], there
has been no report studying its efficacy in more than 100 cases in an Asian population.
In this retrospective study, we aimed to investigate the effectiveness of mazindol byanalyzing changes in body weight and the rate of body weight change. By retrospectively
examining our data, we sought to contribute to the existing body of evidence on mazindol
and to provide insights into the clinical efficacy of mazindol as an anorexiant agent forseverely obese patients in Japan.
2. Materials and Methods
Study design: This retrospective study aimed to evaluate the effectiveness of mazindol
therapy in patients with severe obesity (i.e., BMI over 35). Patients who received mazindol
treatment between August 2013 and April 2021 were enrolled consecutively. The inclusion
criteria included a BMI over 35 and a minimum prescription term of 90 days. Patients witha history of metabolic and bariatric surgeries and those with insufficient clinical data were
excluded from the analysis. Additionally, patients with a history of diseases contraindicatedfor mazindol, such as mental disorders including eating disorders, glaucoma, severe heartdisease, severe pancreatic disease, severe kidney disease, severe liver diseases, drug andalcohol addiction, and severe hypertension, were excluded.
Mazindol therapy: Prior to initiating mazindol therapy, the patients’ baseline biochemical data were evaluated through blood samples. The patients were prescribed mazindol(FUJIFILM Toyama Chemical Co., Ltd., Tokyo, Japan) at a dosage of 0.5–1.5 mg once aday, to be taken before lunch. The prescription was repeated every two weeks for a totalof 3 months, followed by a rest period of 3 months or more. The treatment was repeateddepending on the patients’ preferences.
Weight assessment: The patients were categorized into four groups according to their
number of treatment cycles, and the reduction in their body weight was assessed before
and after they completed the treatment. The change in body weight (CBW) was calculated
by subtracting their weight at the beginning from their weight at the end of each treatment
cycle. The percentage change in body weight (%CBW) was calculated by determining thepercentage of weight change relative to their baseline weight.
Data analysis: Descriptive statistics were used to summarize the quantitative variables,
which are presented as mean values accompanied by standard errors. The categoricalvariables were summarized as percentages. Statistical significance was determined using a p-value threshold of less than 0.05. For the comparisons of background factors
among groups, Fisher’s exact test was employed for nominal variables. Additionally, theKruskal−Wallis test was used for continuous variables. For the pairwise comparison, theBonferroni test was conducted. The correlation between the CBW (or %CBW) and thecontinuous variables was assessed using the Spearman’s rank correlation method. The
relationship between the CBW (or %CBW) and the nominal variables, such as sex, comorbidities, and medications, was compared using the Mann−Whitney U test. The data
analysis was conducted using the EZR software (version 1.61, Saitama Medical Center, Jichi
Medical University, Saitama, Japan), which provides a user-friendly interface for statistical analysis. The software incorporates R (version 4.3.1, The R Foundation for StatisticalComputing, Vienna, Austria) and the R commander (version 2.9-0, McMaster University,
Hamilton, ON, Canada), allowing for the implementation of a wide range of statistical tests
and procedures.

J. Clin. Med. 2024, 13, 1860

University, Saitama, Japan), which provides a user-friendly interface for statistical analysis. The software incorporates R (version 4.3.1, The R Foundation for Statistical Computing, Vienna, Austria) and the R commander (version 2.9-0, McMaster University, Hamilton, ON, Canada), allowing for the implementation of a wide range of statistical tests andprocedures.
3 of 10
3. Results
3.3.1.
Results
Demographic Data
3.1. Demographic Data

Of the total, 202 patients were consecutively enrolled. Among them, 9 were excluded

total, 202patients surgery
were consecutively
enrolled.
them, 9 werea excluded
due Ofto athehistoryof bariatricand 46 dropped
out Amongbefore completing
single 90-day
due
toahistoryofbariatric
surgeryand46
droppedout
beforecompletinga single 90-day
treatment cycle (2 due to insomnia, 1 due to anxiety, 1 due to gastric discomfort,
1 due totreatment cycle (2 due to insomnia, 1 due to anxiety, 1 due to gastric discomfort, 1 due toconstipation, 4 due to living in a distant place, 1 moved to another clinic, 3 were hospitalconstipation, 4 due to living in a distant place, 1 moved to another clinic, 3 were hospitalized
ized for other diseases, and 33 for unknown reasons) (Figure 1). As a result, a total of 147
for other diseases, and 33 for unknown reasons) (Figure 1). As a result, a total of 147 patientspatients were included in the retrospective analysis. The patients were categorized into
were included in the retrospective analysis. The patients were categorized into four groups
four groups
based onnumberof treatment
cycles they
underwent
cycle,
2 cycles,basedon the number
ofthe
treatment
cyclesthey underwent(1 cycle,
2 cycles,(13–5cycles,and 3–
5
cycles,andover6cycles).
over 6 cycles).

Figurestudy
subjects.
Initially,
202202
patients
werewere
consecutively
enrolled.
Of Of
Figure1.1.Enrollment
Enrollmentofofthe
the
study
subjects.
Initially,
patients
consecutively
enrolled.
these,
were
excludeddue toa historyof bariatricsurgery. surgery.
A total of A
46 totalpatients
wereunable werethese,9 9patientspatients
were
excludeddue
to a historyof bariatricof 46
patients
tocompletea single 90-day
treatment
cycle (The causesof treatment
andcessation
number ofcases
unableto completea single
90-day treatment
cycle (Thecauses ofcessation
treatment
andnumberare
indicated
the sameinbox).
147 patientsthe subjected
retrospectiveof cases
are inindicated
the Finally,same box).
Finally,were147 subjectedpatients towereto analysis.
the retrospective

analysis.

3.2. Baseline Characteristics
The numberof patients in each group was as follows: n = 77 (1 cycle), n = 35 (2 cycles),3.2. Baseline
Characteristics
n = 22 (3–5 cycles), and n = 13 (over 6 cycles) as indicated in Table 1. The BMI values
The number of patients in each group was as follows: n = 77 (1 cycle), n = 35 (2 cycles),were significantly higher in the over-six-cycle group compared to one-cycle and two-cyclen = 22 (3–5 cycles), and n = 13 (over 6 cycles) as indicated in Table 1. The BMI values weregroups. The prevalence of HL was significantly lower in the one-cycle group than thesignificantly group,
higher andin thegroup
compared
to one-cycle
and two-cycle
over-six-cycle
SASover-six-cycle
was significantly
lower
in the one-cycle
group comparedgroups.
The
prevalence
of
HL
was
significantly
lower
in
the
one-cycle
group
than
to all other groups. The use of statins differed among groups, although there
wasthenooversix-cycle
group,
andSAS
wassignificantly
lower
in
the
one-cycle
group
compared
to allsignificant difference among groups upon pairwise comparison.

other groups. The use of statins diﬀered among groups, although there was no significant
diﬀerence among groups upon pairwise comparison.
Table 1. Baseline characteristics of the subjects in this study.

J. Clin. Med. 2024, 13, 1860

4 of 10

Table 1. Baseline characteristics of the subjects in this study.
PairwiseComparison

Clinical Parameters

1 Cycle2 Cycles

3–5 Cycles

Over 6 Cycles

p-Value

n

77

35

22

13

−

Age (years)
Sex (male/female)
Height (cm)Weight (kg)44.1 ± 1.441/36
164 ± 1.0
110 ± 2.6

45.0 ± 2.1
23/12
165 ± 1.7
111 ± 4.1

44.8 ± 2.9
13/9
165 ± 1.8
123 ± 6.6

53.3 ± 3.4
4/9
163 ± 2.1
124 ± 7.4

0.14
0.55
0.86
0.09

BMI

40.8 ± 0.8

40.5 ± 0.944.5 ± 1.7

46.8 ± 2.3

0.004

BS (mg/dL)
HbA1c (%)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
LDL cholesterol (mg/dL)
HDL cholesterol (mg/dL)
Triglyceride (mg/dL)
Uric acid (mg/dL)
AST (IU/L)
ALT (IU/L)

125 ± 5.6
6.6 ± 0.2
140 ± 2.0
85 ± 1.4
120 ± 4.1
48 ± 1.2
178 ± 115.9 ± 0.2
32 ± 1.7
44 ± 3.4

106 ± 4.1
6.1 ± 0.1
135 ± 3.1
83 ± 1.8
123 ± 4.7
50 ± 1.8178 ± 20
6.2 ± 0.2
42 ± 4.960 ± 8.9117 ± 9.4
6.0 ± 0.3
140 ± 3.987 ± 2.3
128 ± 6.4
49 ± 1.9
146 ± 155.6 ± 0.3
27 ± 2.4
34 ± 4.6132 ± 16.6
6.6 ± 0.3
140 ± 3.6
86 ± 3.7
115 ± 3.9
48 ± 2.9145 ± 195.5 ± 0.3
30 ± 3.436 ± 3.5

0.22
0.10
0.68
0.98
0.65
0.71
0.33
0.20
0.16
0.60

n.s.
n.s.
n.s.
n.s.
1 cycle, 2 cycles <over 6 cycles *
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.

Diabetes mellitus (%)

33(42.9)

13(37.1)

11(50.0)9(69.2)

0.23

n.s.

Hypertension (%)

30(39.0)16(45.7)

13(59.1)

8(61.5)

0.22

n.s.

Hyperlipidemia (%)

18(23.4)

19(54.3)

12(54.5)

11(84.6)<0.001

1 cycle < 2 cycles,
3–5 cycles *, 1 cycle< over 6 cycles ***Sleep apnea syndrome (%)

10(13.0)17(48.6)

13(59.1)

9(69.2)<0.001

1 cycle < 2 cycles,
3–5 cycles, over 6
cycles ***Biguanide (%)

16(20.8)8(22.9)6(27.3)6(46.2)

0.26

n.s.

SGLT2 inhibitor (%)

16(20.8)

7(20.0)2(9.1)

5(38.5)

0.25

n.s.

DPP4 inhibitor (%)

7(9.1)

3(8.6)

2(9.1)

3(23.1)

0.45

n.s.

GLP1 receptor agonist (%)

5(6.5)

4(11.4)3(13.6)2(15.4)

0.45

n.s.

SU (%)

6(7.8)

1(2.9)0(0)1(7.7)

0.44

n.s.

Insulin (%)

6(7.8)0(0)0(0)

2(15.4)

0.06

n.s.

Angiotensin receptor blocker (%)

24(31.2)9(25.7)7(27.3)8(61.5)

0.14

n.s.

Calcium channel blocker (%)

22(28.6)

5(14.3)6(27.3)6(46.2)

0.13

n.s.

Statin (%)

13(16.9)5(14.3)9(40.9)6(46.2)

0.01

n.s.

Comorbidities

Medications

Data are expressed as mean ± SE, numbers, or as frequencies (%). *: p < 0.05, ***: p > 0.001. n.s.: not significant

3.3. Change in Body Weight (CBW) and Percent Change in Body Weight (%CBW)
The changes in body weight observed in each treatment group were as follows:−6.5 ± 0.5 kg for 1 cycle; −7.7 ± 1.4 kg for 2 cycles; −12.8 ± 2.4 kg for 3–5 cycles; and−15.4 ± 3.3 kg for over 6 cycles (Figure 2a). The percent change in body weight observedin each treatment group was as follows: −5.6 ± 0.4% for 1 cycle; −6.5 ± 1.0% for 2 cycles;−10.4 ± 1.6% for 3–5 cycles; and −11.6 ± 2.3% for over 6 cycles (Figure 2b). In both CBW
and %CBW values, we observed a significant increase in the effectiveness of the treatmentin the over-six-cycle group compared to the one-cycle group. Additionally, we noted asignificant increase in the 3–5-cycle group compared to the 1-cycle and 2-cycle groups.
Overall, the effectiveness of the treatment seemed to increase as the patients went throughmultiple cycles.

J. Clin. Med. 2024, 13, x FOR PEER REVIEW

5 of 10

J. Clin. Med. 2024, 13, x FOR PEER REVIEW

J. Clin. Med. 2024, 13, 1860

5 of 10

eﬀectiveness of the treatment seemed to increase as the patients went through multiple
cycles.
5 of 10
eﬀectiveness of the treatment seemed to increase as the patients went through multiple
cycles.

(a)(b)

Figure 2. Eﬀectiveness of mazindol therapy in each group divided by the number of treatment cycles(a)(b)
performed. Graph (a) shows the changes in body weight (in kg), and graph (b) shows the proportions2.ofthebody weightchangestherapy(aspercentages).
Figureofofmazindol
inin
each
group
dividedbyby
thenumberofof
treatment
cyclesFigure
2.Eﬀectiveness
Effectivenessmazindoltherapyeach
group
dividedthenumbertreatment
cyclesperformed.
shows thethe changes
changesin
inbodybodyweightweight(in(inkg),kg),andandgraph
graph
shows
proporperformed.Graph
Graph (a)(a) shows(b)(b)
shows
thetheproportions
tions
ofFactors
the body
weightchanges(asInfluencing
CBW
andpercentages).
%CBWof3.4.
thebodyweightchanges(as percentages).

Next, we investigated the factors influencing the CBW. Among them, the initial body
3.4.
Factors
Influencing
CBW
and%CBW%CBW
3.4.
Factors
Influencing
CBWandweight(Figure3a) andinitialBMI(Figure 3b) were found to be correlated with the CBW.
Next,
weinvestigatedthefactors
influencing
theCBW.
CBW.Among
Amongthem,thetheinitialbody
we investigated
the factors
influencing
them,
initialbody
AsNext,patients
with higher bodyweighttended tothe
undergomoretreatment
cycles,weanaweight(Figure3a)of
and
initial BMI
BMI(Figure
found
be
with
CBW.
As
weight3a)andinitial(Figurewere
foundtoamong
becorrelated
correlated
withthetheCBW.
lyzed(Figure
the
eﬀect
mazindolwithinthe 3b)firstwere
singlecycleto141 patients
whose
data
patients
withhigherweighttendedto undergo
moretreatment
cycles,analyzedAspatients
withhigherbody
weighttendedtoweight
undergomoretreatment
cycles,weanawereavailable.
As abody
result,the initial
body
still
correlated
with
thewe
CBW
after atheeffectof mazindol
thesinglecyclecycleamong
141 patients
whose
were
lyzed
thetreatmenteﬀect
of mazindol
withinthefirstsingle
among
141
data
singlecycle within(Figure3c).first
However,when
we analyzed
thepatients
eﬀect
ofwhosethedatatreatment
available.
Asaresult,theinitialbody
weightstill
correlated
with
the
CBW
after
a
singlewereavailable.
Asaresult,theinitialbody
weightstill
correlated
with
the
CBW
after
a
on %CBW, we did not find this correlation (Figure 3d–f).
treatment
cycle(Figure3c).
However,when
weanalyzedtheeffectofthetreatmentonsingle treatment cycle (Figure 3c). However, when we analyzed the eﬀect of the treatment
%CBW,
wewe
did
not
find
this
correlation(Figure3d–f).
on
%CBW,
did
not
find
this
correlation(Figure3d–f).

(a)Figure(a) 3. Cont.

(b)
(b)

J. Clin. Med. 2024, 13, x FOR PEER REVIEW

6 of 10

J. Clin. Med. 2024, 13, 1860

6 of 10

(c)

(d)

(e)

(f)

Figure3.3.Relationship
Relationshipbetween
betweenthe
theeffecteﬀectofofmazindol,
mazindol,thetheinitial
initialbody
bodyweight,
weight,and
andBMI.The
BMI.Theupper
upper
Figuretwopanelsshow
therelationshipbetweenchangesinbodyweight(CBWs)
andinitialbody
weighttwo panels show the relationship between changes in body weight (CBWs) and initial body weight(a) or initial BMI (b). To exclude the eﬀect of the number of treatment cycles, we analyzed the rela(a) or initial BMI (b). To exclude the effect of the number of treatment cycles, we analyzed thetionship between the initial body weight and CBWs only within the first cycle (c). In the latter three
relationship between the initial body weight and CBWs only within the first cycle (c). In the latter
panels, the same analyses were performed, but only CBWs are replaced with percent change in bodythreepanels,the(f).
same
analyses
werecorresponds
performed, but
onlypatient.)
CBWs are replaced with percent change inweight(d), (e),(Theblue circle
to eachbody weight (d–f). (The blue circle corresponds to each patient.)

Additionally, in patients with sleep apnea syndrome (SAS), the CBW was found to
Additionally, in patients with sleep apnea syndrome (SAS), the CBW was found to be
be more pronounced; meanwhile, other comorbidities, laboratory factors, and medicamore pronounced; meanwhile, other comorbidities, laboratory factors, and medications
tions were not shown to aﬀect the CBW (Figure S1). As the initial body weight may be awere not shown to affect the CBW (Figure S1). As the initial body weight may be a
confounding factor for the CBW, we divided the CBW by the initial body weight (which
confounding factor for the CBW, we divided the CBW by the initial body weight (whichis equal to the %CBW) and compared these values among patients with or without SAS;is equal to the %CBW) and compared these values among patients with or without SAS;
consequently, we found no significant diﬀerence between the two groups (Figure S2).
consequently, we found no significant difference between the two groups (Figure S2).
(Data analyzing the relationships between the clinical factors and the CBW are shown in(Data analyzing the relationships between the clinical factors and the CBW are shown in
a supplementary file as Figure S1. Data analyzing the relationship between SAS and thea supplementary file as Figure S1. Data analyzing the relationship between SAS and the
CBW or %CBW are shown in Figure S2.)
CBW or %CBW are shown in Figure S2.)
Discussion
4.4.Discussion
Inthisthisanalysis
analysisofof147
147
cases
mazindolin Japan,we examinedthe extent
and
In
cases
of of
mazindoluseusein Japan,we examinedthe extent
and rate
rate
of
body
weightchanges.
The
results
of
this
study
highlight
thesignificanceofmazinof body weight changes. The results of this study highlight the significance of mazindol asa potential treatment option for severely obese patients. The data clearly demonstrate that

J. Clin. Med. 2024, 13, 1860

7 of 10the efficacy of mazindol in reducing body weight increases with the number of treatment
cycles that the patient undergoes. While a significant correlation was observed betweenchanges in body weight and the initial body weight, such a correlation was not found withthe percentage change in body weight. As patients with a larger initial body weight tended
to undergo more treatment cycles, we chose to analyze these correlations within a single
treatment cycle. The results still show a significant correlation between changes in bodyweight and the initial body weight, but not in the percentage change in body weight. Thesefindings suggest that patients who continue mazindol therapy over multiple cycles are
more likely to achieve a substantial weight loss, maintaining a consistent ratio irrespectiveof the initial body weight. In light of said findings, mazindol may be a valuable therapeutic
approach for individuals struggling with severe obesity.
Since mazindol has only been approved and used in limited regions, such as Japan,
Canada, Brazil, and Mexico, among others, reports on the efficacy and safety of mazindolthat feature a substantial number of cases remain rare. In 2022, reports from Mexico
comparing the effects of mazindol with or without the concurrent use of metformin in
137 cases showed weight reductions of approximately 7–8% after 3 months of mazindol use
and of 9–11% after 6 months of use [17]. Similarly, a 2022 report from Mexico involving 196
cases reported weight reductions of approximately 8.0% after 3 months of mazindol use
and 10.7% after 6 months of use [18]. These reports indicate more pronounced reductions
in weight when compared to the current study.
The differences in these effects may be influenced by several factors. In our study,
most patients received a dosage of 0.5 mg of mazindol, while in previous studies in
Mexico, 1.0 mg was administered in all cases. Additionally, the proportion of females inour study was 55%, while in the previous studies, it exceeded 80%. These differences,along with potential racial variations, may have contributed to the observed variations
in weight reduction effects, although we did not find any gendered difference in bodyweight reduction.
It is important to note that the absolute body weight change exhibited a statisticallysignificant negative correlation with the initial body weight and BMI. Furthermore, todistinguish the effect of duration, we analyzed the relationship between changes in weight
before and after the first treatment cycle in all 141 cases whose data were available; therefore, we found that significant negative correlations were preserved. However, these
correlations were lost when we used the percentage change in body weight as a marker oftherapeutic effect. The results suggest that the body weight-reducing effect of mazindol is
proportionally similar, irrespective of the pretreatment body weight.
When observing the overall results of this study, we can suggest that the therapeutic
effect of mazindol leads to a consistent weight loss regardless of the initial body weight.
Even in patients with a higher body weight, achieving their target body weight may bepossible after multiple treatment cycles.
While previous reports have indicated that the weight reduction effects of mazindol
are enhanced when the drug is used in combination with metformin [17], it is noteworthy
that, in our study, there was no significant difference observed between the group receiving
the metformin treatment and the group not receiving the metformin treatment. This may be
because of the smaller number of diabetes or prediabetes patients treated with metforminin the current study. Further investigations exploring the potential impact of metformin in
specific subpopulations or treatment regimens are therefore warranted.
Furthermore, our study found no significant impact on absolute weight loss associatedwith the use of GLP-1 receptor agonists or SGLT2 inhibitors as adjuvant therapies.
One limitation of our study was the very low number of patients using these medications. It is also possible that, by the time the mazindol treatment commenced, theweight-reducing effect of these medications had already reached a plateau. While GLP-1
receptors are expressed in multiple areas in the brain, such as the parietal cortex, hypothalamus, and brain medulla [19], mazindol’s sites of action are located in the hypothalamic
lateral nucleus and the hypothalamic ventromedial nucleus [20,21], meaning a disparity inJ. Clin. Med. 2024, 13, 1860

8 of 10these drugs’ action sites. SGLT2 inhibitors act in the proximal tubules of the kidney [22].
Due to these differences in action sites, we anticipate a synergistic effect of mazindol whenused in combination with these medications. Further investigations involving a larger
number of cases are warranted in the future.
It is important to acknowledge that the influence of these medications on weight
reduction outcomes may be affected by various factors, including the specific patient
population, dosages, and treatment regimens. While our study did not identify a substantial
effect on weight loss related to the use of these medications, further research may benecessary to explore their potential impact on specific patient subsets under different
treatment conditions.
On the other hand, it was found that patients with SAS demonstrated greater reductions in weight. As the group with SAS had significantly larger initial body weight values,
we divided the CBW by the initial body weight and compared the results among the twogroups; thus, we found no significant difference. This suggests that the factor of initial
body weight plays a more substantial role in the effects of mazindol.
Recently, semaglutide has been approved as an anti-obesity drug in Japan; it is thefirst drug of its kind to be authorized in the decades following the approval of mazindol.
However, there do exist concerns about weight regain after the cessation of treatment. Combining mazindol with semaglutide may offer a solution for long-term weight management
without significant rebounding effects.
Our study is unique in that it evaluated the effect of mazindol over an extended
period of six cycles or more, contributing to its novelty. Since evidence of mazindol’s
effect in Asian populations is limited, with the existing sample sizes ranging from 13 to 36
cases [23,24], the current study may contribute to establishing a new body of evidence forthe effectiveness of mazindol in Asian populations.
In Japan, the administration of mazindol mandates bi-weekly clinic visits within athree-month drug cycle, followed by a rest period of over three months before the next
cycle. This regimen prevents patients from cessation, helps to maintain motivation, andmay contribute to long-term weight reduction effects.
Limitations
This retrospective observational study was conducted within authentic clinical settings,
lacking a randomized case–control design. Consequently, the absence of a placebo groupposes challenges in discerning the genuine impact of the drug from other factors, such as
the placebo effect, dietary restrictions, or exercise effects. A more refined evaluation of theeffectiveness of mazindol necessitates a randomized case–control study.
5. Conclusions
In conclusion, this retrospective study demonstrates that mazindol may be an effective
option for reducing body weight in severely obese patients. The treatment’s efficacy
is positively correlated with the number of treatment cycles undertaken, highlighting
the importance of continued therapy in the pursuit of optimal results. These findings
contribute to our understanding of mazindol’s role in the management of severe obesityand emphasize the need for further research to explore its long-term effects and impact on
obesity-related comorbidities.
Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm13071860/s1. Figure S1: Relationship between the CBW andcomorbidities, laboratory factors, and medications. Figure S2: Effect of SAS on the CBW and %CBW.
Author Contributions: Conceptualization, K.M.; methodology, Y.T. and K.M.; software, Y.T.; validation, Y.T.; formal analysis, Y.T.; investigation, Y.T., N.M., M.K. and K.M.; resources, Y.T.; data curation,
Y.T. and K.M.; writing—original draft preparation, Y.T.; writing—review and editing, N.M., M.K. andK.M.; visualization, Y.T.; supervision, N.M., M.K. and K.M; project administration, K.M.; funding
acquisition, K.M. All authors have read and agreed to the published version of the manuscript.

J. Clin. Med. 2024, 13, 1860

9 of 10

Funding: This research received no external funding except for the APC, which was funded by
Fujifilm. Toyama Chemical Co., Ltd.
Institutional Review Board Statement: The study was conducted in accordance with the Declarationof Helsinki. The study protocol was approved by the Japan Medical Association Ethics Review
Committee (protocol code R3-04, date of approval, 28 May 2021).
Informed Consent Statement: Informed consent was obtained from all subjects involved.
Data Availability Statement: The raw data supporting the conclusions of this article will be madeavailable by the authors upon request.
Conflicts of Interest: The funders had no role in the design of the study; in the collection, analyses,
or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

References
1.

2.
3.
4.
5.

6.
7.
8.

9.
10.

11.
12.
13.
14.
15.
16.
17.

18.

NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: A pooled
analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 2016, 387, 1377–1396. [CrossRef][PubMed]Nguyen, N.T.; Nguyen, X.-M.T.; Lane, J.; Wang, P. Relationship Between Obesity and Diabetes in a US Adult Population: Findings
from the National Health and Nutrition Examination Survey, 1999–2006. Obes. Surg. 2011, 21, 351–355. [CrossRef]
Colditz, G.A.; Willett, W.C.; Rotnitzky, A.; Manson, J.E. Weight Gain as a Risk Factor for Clinical Diabetes Mellitus in Women.
Ann. Intern. Med. 1995, 122, 481–486. [CrossRef]
Carmo, J.M.D.; da Silva, A.A.; Wang, Z.; Fang, T.; Aberdein, N.; de Lara Rodriguez, C.E.; Hall, J.E. Obesity-Induced Hypertension:
Brain Signaling Pathways. Curr. Hypertens. Rep. 2016, 18, 58. [CrossRef] [PubMed]
Nordestgaard, B.G.; Palmer, T.M.; Benn, M.; Zacho, J.; Tybjærg-Hansen, A.; Smith, G.D.; Timpson, N.J. The Effect of Elevated
Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach. PLoS Med. 2012,
9, e1001212. [CrossRef] [PubMed]
Flegal, K.M.; Graubard, B.I.; Williamson, D.F.; Gail, M.H. Cause-Specific Excess Deaths Associated with Underweight, Overweight,
and Obesity. JAMA 2007, 298, 2028–2037. [CrossRef]
Balachandran, J.S.; Masa, J.F.; Mokhlesi, B. Obesity Hypoventilation Syndrome: Epidemiology and diagnosis. Sleep Med. Clin.
2014, 9, 341–347. [CrossRef] [PubMed]
Harada, Y.; Chihara, Y.; Azuma, M.; Murase, K.; Toyama, Y.; Yoshimura, C.; Oga, T.; Nakamura, H.; Mishima, M.; Chin, K.; et al.
Obesity hypoventilation syndrome in Japan and independent determinants of arterial carbon dioxide levels. Respirology 2014, 19,1233–1240. [CrossRef]
Müller, T.D.; Clemmensen, C.; Finan, B.; DiMarchi, R.D.; Tschöp, M.H. Anti-Obesity Therapy: From Rainbow Pills to Polyagonists.
Pharmacol. Rev. 2018, 70, 712–746. [CrossRef]
Kimura, Y.; Fujishima, Y.; Nishizawa, H.; Saito, T.; Miyazaki, Y.; Shirahase, K.; Tokuzawa, C.; Nagai, N.; Fukuda, S.; Maeda, K.;
et al. Changes in Eating Behaviors and Their Associations with Weight Loss in Japanese Patients Who Underwent Laparoscopic
Sleeve Gastrectomy. Nutrients 2023, 15, 353. [CrossRef]
Altieri, M.S.; Yang, J.; Nie, L.; Blackstone, R.; Spaniolas, K.; Pryor, A. Rate of revisions or conversion after bariatric surgery over 10
years in the state of New York. Surg. Obes. Relat. Dis. 2018, 14, 500–507. [CrossRef]
Tolvanen, L.; Christenson, A.; Surkan, P.J.; Lagerros, Y.T. Patients’ Experiences of Weight Regain After Bariatric Surgery. Obes.
Surg. 2022, 32, 1498–1507. [CrossRef]
Alyahya, R.; A Alnujaidi, M. Prevalence and Outcomes of Depression After Bariatric Surgery: A Systematic Review andMeta-Analysis. Cureus 2022, 14, e25651. [CrossRef]
Adams, T.D.; Gress, R.E.; Smith, S.C.; Halverson, R.C.; Simper, S.C.; Rosamond, W.D.; LaMonte, M.J.; Stroup, A.M.; Hunt, S.C.
Long-Term Mortality after Gastric Bypass Surgery. New Engl. J. Med. 2007, 357, 753–761. [CrossRef]
Japan Society for the Study of Obesity. Guidelines for the Management of Obesity Disease 2022; Life Science Publishing Company:
Tokyo, Japan, 2022. (In Japanese)
Cunha, J.B.; Fialho, M.C.M.P.; Arruda, S.L.M.; Nóbrega, O.T.; Camargos, E.F. Clinical and Metabolic Improvement after BariatricSurgery in Older Adults: A 6-Year Follow-Up. J. Nutr. Health Aging 2020, 24, 865–869. [CrossRef]
Arguelles-Tello, F.A.; Kammar-García, A.; Trejo-Jasso, C.A.; Huerta-Cruz, J.C.; Barranco-Garduño, L.M.; Rocha-González, H.I.;
Reyes-García, J.G. Metformin improves the weight reduction effect of mazindol in prediabetic obese Mexican subjects. Int. J. Clin.
Pharmacol. Ther. 2022, 60, 336–345. [CrossRef] [PubMed]
Huerta-Cruz, J.C.; Rocha-González, H.I.; Kammar-García, A.; Canizales-Quinteros, S.; Barranco-Garduño, L.M.; Reyes-García, J.G.
Combined First Month Body Weight Loss and Development of Tolerance as Predictors of 6-Month Efficacy of Mazindol in Mildand Moderate Obese Subjects. J. Clin. Med. 2022, 11, 3211. [CrossRef]

J. Clin. Med. 2024, 13, 1860

19.

20.
21.
22.
23.
24.

10 of 10

Farr, O.M.; Sofopoulos, M.; Tsoukas, M.A.; Dincer, F.; Thakkar, B.; Sahin-Efe, A.; Filippaios, A.; Bowers, J.; Srnka, A.; Gavrieli,
A.; et al. GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue
liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: A crossover, randomised,
placebo-controlled trial. Diabetologia 2016, 59, 954–965. [CrossRef] [PubMed]
Hetherington, A.W.; Ranson, S.W. Hypothalamic lesions and adiposity in the rat. Anat. Rec. 1940, 78, 149–172. [CrossRef]
Anand, B.K.; Brobeck, J.R. Localization of a “Feeding Center” in the Hypothalamus of the Rat. Exp. Biol. Med. 1951, 77, 323–325.
[CrossRef] [PubMed]
Kanai, Y.; Lee, W.S.; You, G.; Brown, D.; Hediger, M.a. The human kidney low affinity Na+/glucose cotransporter SGLT2.
Delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Investig. 1994, 93, 397–404. [CrossRef] [PubMed]
Nishikawa, T.; Iizuka, T.; Omura, M.; Kuramoto, N.; Miki, T.; Ito, H.; Chiba, S. Effect of Mazindol on Body Weight and Insulin
Sensitivity in Severely Obese Patients after a Very-Low-Calorie Diet Therapy. Endocr. J. 1996, 43, 671–677. [CrossRef] [PubMed]
Yoshida, T.; Sakane, N.; Umekawa, T.; Yoshioka, K.; Kondo, M.; Wakabayashi, Y. Usefulness of mazindol in combined diet therapy
consisting of a low-calorie diet and Optifast in severely obese women. Int. J. Clin. Pharm. Res. 1994, 14, 125–132.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury topeople or property resulting from any ideas, methods, instructions or products referred to in the content.